Palonosetron is a selective 5-HT3 antagonist marketed commercially as Aloxi® for the treatment of emesis. The chemical name of the compound is (3aS)-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hberiz[de]isoquinoline, as depicted by the following chemical structure of the hydrochloride salt:

Methods of synthesizing palonosetron are described in U.S. Pat. Nos. 5,202,333 and 5,510,486. Pharmaceutically acceptably dosage forms are described in PCT publications WO 2004/067005 and WO 2008/049552 from Helsinn Healthcare.
Netupitant is a selective NK1 receptor antagonist of the formula 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide, or Benzeneacetamide, N,α,α-trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3,5-bis(trifluoromethyl)-, having the below chemical structure:

Methods of synthesizing and formulating netupitant and its prodrugs are described in U.S. Pat. Nos. 6,297,375, 6,719,996 and 6,593,472 to Hoffmann La Roche.
Several prior art references disclose the combined use of an NK1 receptor antagonist and a 5-HT3 receptor antagonist for the treatment of emesis. Roila et al. report that the co-administration of a NK1 receptor antagonist, such as aprepitant, at the same time as a 5-HT3 antagonist, significantly increases the efficacy of 5-HT3 antagonists in preventing both acute and delayed CINV. See Roila F, Fatigoni S (2006) NEW ANTIEMETIC DRUGS. Ann Oncol 17 Suppl 2: ii96-100. Roche reported in 2006 that “[s]ince 5HT3 and NK1 receptor antagonists exert additive effects [on nausea and vomiting] there is considerable potential for the combined use of Aloxi and netupitant.” See NK1 receptor antagonists by Roche, Feb. 23, 2006, http://www.hospitalpharma.com/Features/feature.asp?ROW_ID=742.
Palonosetron and other 5HT3 receptor antagonists were developed originally for the prevention of emesis, but more recently have received attention for their role in pain signaling and transmission in the peripheral and central nervous systems. 5HT3 receptors are known to mediate a descending facilitatory influence on spinal cord activity, a constituent drive that is particularly prominent on mechanical and chemical evoked activity. There is enhancement of this activity following peripheral nerve injury, spinal cord injury and after intense chemical stimulation. A number of studies using opioid-induced-hyperalgesia and activation of ERK support the concept of descending 5HT3 facilitation as a target for pain control. See, e.g., G H McCleane, et al., ANETH ANALG 2003; 97: 1474-8 (reporting that “5HT3 receptors play a pronociceptive role and mediate descending excitatory controls that allow spinal neurons to fully code peripheral stimuli.”)
Spinal NK1 receptors are part of the post-synaptic targets for neurotransmitter released from afferent terminals, and also have been studied for their role in pain. See De Felipe C, et al. (March 1998) NATURE 392 (6674): 394-7 (reporting that “the peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system.”) L M Thomson et al. (2008 January) J PAIN; 9(1): 11-19 (reporting that substance P systems “may also represent important therapeutic targets for the retention and restoration of pain relief with prolonged morphine treatment.”)
Only about 15% of afferents release substance P and this may be reduced after nerve injury although some studies report a phenotypic switch of the transmitter to large fibers. Thus, while several prior art references implicate NK1 receptors in the pain signaling process, considerable doubt has emerged as to the viability of NK1 receptor antagonists to successfully treat pain in human patients. As Hill stated in 2000, “NK1 receptor antagonists have failed to exhibit efficacy in [human] clinical trials of a variety of clinical pain states.” See R Hill (July 2000) TRENDS IN PHARMACEUTICAL SCIENCES Vol. 21, pages 244-246. So, the target alone might not be relevant in controlling the pain processing.
Irritable bowel syndrome (IBS), a functional bowel disorder, is a syndrome characterized by abdominal discomfort or pain associated with defecation and abnormal bowel movement in spite of the absence of a detectable intestinal organic disease. The symptoms include diarrhea, abdominal pain, abdominal bloating, and constipation, and are classified into a diarrhea type (IBS-D), a constipation type (IBS-C), and an alternating diarrhea and constipation type (IBS-A). The symptoms may be accompanied by a psychological condition such as anxiety, hypersensitivity, tension, fretfulness, depression, or the like.
The precise pathophysiology of IBS remains to be elucidated. Nevertheless, there is a heightened sensitivity to visceral pain perception, known as peripheral sensitization. This sensitization involves a reduction in the threshold and an increase in the gain of the transduction processes of primary afferent neurons, attributable to a variety of mediators including monoamines (e.g., catecholamines and indoleamines), substance P, and a variety of cytokines and prostanoids such as E-type prostaglandins (see, e.g., Mayer et al., Gastroenterol., 107:271-293 (1994)). Also implicated in the etiopathology of IBS is intestinal motor dysfunction, which leads to abnormal handling of intraluminal contents and/or gas (see, e.g., Kellow et al., Gastroenterol., 92:1885-1893 (1987); Levitt et al., Ann. Int. Med., 124:422-424 (1996)). Psychological factors may also contribute to IBS symptoms appearing in conjunction with, if not triggered by, disturbances including depression and anxiety (see, e.g., Drossman et al., Gastroenterol. Int., 8:47-90 (1995)).
Although no animal models of IBS exist, advances in the understanding of the pathophysiology of IBS have facilitated the development of preclinical rodent models of visceral hypersensitivity. The method of colorectal distention (CRD) can be used to activate nociceptive neuronal pathways from the gastrointestinal (GI) tract, which induces a protective reflex of abdominal muscle contraction (see, e.g., Ness et al., Brain Research, 450: 153-169 (1988)). One method of measuring these contractions is via strain gauges sutured onto the abdominal muscle (see, e.g., Plourde et al., American Journal of Physiology, 273: G191-196 (1997)). Colonic hypersensitivity can be induced experimentally in a rodent model by infusing dilute acetic acid (0.6%) into the colon which causes a transient sensitization of colonic sensory afferents which results in an increase in the VMR to CRD (see e.g., Gaudreau et al., Neuroscience Letters, 351 (2): 59-62 (2003); Venkova et al., Toxicology and Applied Pharmacology, 196: 215-222 (2004)). Although heightened visceral pain perception is well demonstrated in IBS, the existence of abnormalities in somatic pain is controversial with more recent reports suggesting enhanced somatic sensitivity in IBS through viscero-somatic convergence at the level of the spinal cord (see e.g., Chang, Gastroenterology Clinics of North America, 34 (2): 271-2792005; Zhou et al., Pain, 148 (3): 454-461 (2010)).
The gastrointestinal function is highly regulated by the nerves, and a variety of receptors are present. Therefore, an anticholinergic agent, an antidiarrheal, or a laxative is administered according to the gastrointestinal symptoms such as an abdominal pain, diarrhea, and constipation, and an antidepressant or an antianxiety agent is used if needed. Although alosetron HCl, a serotonin 5-HT3 receptor antagonist, is known as a therapeutic agent for diarrhea-type IBS (IBS-D), this agent is applied only to woman patients with severe symptoms because serious gastrointestinal disorders, particularly ischemic colitis and serious constipation, are observed. Further, although tegaserod maleate, a serotonin 5-HT4 receptor agonist, is known as a therapeutic agent for constipation-type IBS (IBS-C), this agent is applied only to women patients. In addition, lubiprostone, a ClC-2 chloride channel activator, is applied only to women patients for constipation-type IBS (IBS-C). Further, Cilansetron, another selective 5-HT3 antagonist, is currently in clinical trials in Europe for the treatment of IBS-D in both men and women; however, in 2005, the sponsor of cilansetron withdrew its application for approval from the US FDA on the basis of a “non-approvable” letter (additional clinical trials were requested). Therefore, the therapeutic options of IBS are limited as the current treatments are gender and IBS subtype specific, and have significant side effects. Therefore, a novel therapeutic agent and method for IBS with no gender or subtype difference and with reduced side effects is strongly desired.